tbuckley/cabot-search huggingface dataset:
Recombinant multimeric dog allergen prevents airway hyperresponsiveness in a model of asthma marked by vigorous <scp>T<sub>H</sub>2</scp> and <scp>T<sub>H</sub>17</scp> cell responses
Authors: Julian M. Stark, Jielu Liu, Christopher A. Tibbitt, Murray Christian, Junjie Ma, Anna Wintersand, Josefine Dunst, Taras Kreslavsky, Ben Murrell, Mikael Adner, Hans Grönlund, Guro Gafvelin, Jonathan M. Coquet
Journal: Allergy (2022)

Abstract Background Allergy to dogs affects around 10% of the population in developed countries. Immune therapy of allergic patients with dog allergen extracts has shown limited therapeutic benefit. Methods We established a mouse model of dog allergy by repeatedly administering dog dander and epithelium extracts via the intranasal route. We also assessed the efficacy of a recombinant multimeric protein containing Can f 1, f 2, f 4 and f 6 in preventing inflammatory responses to dog extracts. Results Repeated inhalation of dog extracts induced infiltration of the airways by T H 2 cells, eosinophils and goblet cells, reminiscent of the house dust mite (HDM) model of asthma. Dog extracts also induced robust airway hyperresponsiveness and promoted T H 17 cell responses, which was associated with a high neutrophilic infiltration of the airways. scRNA‐Seq analysis of T helper cells in the airways pinpointed a unique gene signature for T H 17 cells. Analysis of T‐cell receptors depicted a high frequency of clones that were shared between T H 17, T H 2 and suppressive Treg cells, indicative of a common differentiation trajectory for these subsets. Importantly, sublingual administration of multimeric Can f 1‐2‐4‐6 protein prior to sensitization reduced airway hyperresponsiveness and type 2‐mediated inflammation in this model. Conclusion Dog allergen extracts induce robust T H 2 and T H 17 cell‐mediated responses in mice. Recombinant Can f 1‐2‐4‐6 can induce tolerance to complex dog allergen extracts.
Arterio-ureteral fistula: A nationwide cross-sectional questionnaire analysis
Authors: K. Kamphorst, M.T.W.T. Lock, R.C.N. Van Den Bergh, F.L. Moll, J.P.P.M. De Vries, T.H. Lo, G.A.P. De Kort, R.C.G. Bruijnen, P. Dik, S. Horenblas, L.M.O. De Kort
Journal: European Urology (2022)
Association of Zip Code Vaccination Rate With COVID-19 Mortality in Chicago, Illinois
Authors: Sharon Zeng, Kenley M. Pelzer, Robert D. Gibbons, Monica E. Peek, William F. Parker
Journal: JAMA Network Open (2022)

<h3>Importance</h3> There has been large geographic inequity in vaccination coverage across Chicago, Illinois, with higher vaccination rates in zip codes with residents who predominantly have high incomes and are White. <h3>Objective</h3> To determine the association between inequitable zip code–level vaccination coverage and COVID-19 mortality in Chicago. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used Chicago Department of Public Health vaccination and mortality data and Cook County Medical Examiner mortality data from March 1, 2020, through November 6, 2021, to assess the association of COVID-19 mortality with zip code–level vaccination rates. Data were analyzed from June 1, 2021, to April 13, 2022. <h3>Exposures</h3> Zip code–level first-dose vaccination rates before the Alpha and Delta waves of COVID-19. <h3>Main Outcomes and Measures</h3> The primary outcome was deaths from COVID-19 during the Alpha and Delta waves. The association of a marginal increase in zip code–level vaccination rate with weekly mortality rates was estimated with a mixed-effects Poisson regression model, and the total number of preventable deaths in the least vaccinated quartile of zip codes was estimated with a linear difference-in-difference design. <h3>Results</h3> The study population was 2 686 355 Chicago residents in 52 zip codes (median [IQR] age 34 [32-38] years; 1 378 658 [51%] women; 773 938 Hispanic residents [29%]; 783 916 non-Hispanic Black residents [29%]; 894 555 non-Hispanic White residents [33%]). Among residents in the least vaccinated quartile, 80% were non-Hispanic Black, compared with 8% of residents identifying as non-Hispanic Black in the most vaccinated quartile (P &lt; .001). After controlling for age distribution and recovery from COVID-19, a 10–percentage point increase in zip code–level vaccination 6 weeks before the peak of the Alpha wave was associated with a 39% lower relative risk of death from COVID-19 (incidence rate ratio [IRR], 0.61 [95% CI, 0.52-0.72]). A 10–percentage point increase in zip code vaccination rate 6 weeks before the peak of the Delta wave was associated with a 24% lower relative risk of death (IRR, 0.76 [95% CI, 0.66-0.87]). The difference-in-difference estimate was that 119 Alpha wave deaths (72% [95% CI, 63%-81%]) and 108 Delta wave deaths (75% [95% CI, 66%-84%]) might have been prevented in the least vaccinated quartile of zip codes if it had had the vaccination coverage of the most vaccinated quartile. <h3>Conclusions and Relevance</h3> These findings suggest that low zip code–level vaccination rates in Chicago were associated with more deaths during the Alpha and Delta waves of COVID-19 and that inequitable vaccination coverage exacerbated existing racial and ethnic disparities in COVID-19 deaths.
The euchromatic histone-lysine N-methyltransferases EHMT1/2 suppress post-natal cardiomyocyte proliferation via histone 3 lysine 9 (H3K9) dimethylation
Authors: K Chatzieleftheriadis, MS Sadredini, RDP Donate Puertas, IS Sjaastad, LR Roderick
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): KULeuven C14/17/088 Flemish Research Foundation (FWO) G0C6419N Cardiomyocytes proliferate rapidly during developmental growth in utero, but this proliferative capacity dramatically declines postnatally, rendering the heart unable to repair itself subsequent to injury or during ageing. The mechanisms governing this postnatal loss of cell cycle activity are not fully understood. During maturation, epigenomic remodelling drives wholesale changes in the cardiomyocyte transcriptome from the neonatal to the adult state. This is associated with silencing of foetally-expressed genes and activation of expression of genes required for adulthood. Here, we tested the hypothesis that epigenomic remodelling silences cell cycle-associated genes and hence cell cycle activity postnatally. In this regard, we focused on the role of the repressive H3K9me2 mark. Using immunostaining of Ki-67 and Aurora Kinase B as well as analysis of EdU incorporation to identify cell cycle activity in primary cardiomyocytes culture and in cryosections from rat hearts spanning from embryonic day 18 to adulthood, the abundance of H3K9me2 was found to be inversely correlated with cell proliferation. In line with these data, the expression of a gene panel associated with cell cycle activity decreased postnatally and was inversely related with H3K9me2 abundance in cardiomyocyte nuclei, purified by flow cytometry based on H3K9me2 abundance. Inhibition of the euchromatic histone lysine methyltransferases (Ehmt1/2 aka GLP/G9a), with the highly selective inhibitor A-366, enhanced proliferation of neonatal rat cardiomyocytes in vitro, as well as in vivo, in neonatal mice, via concomitant reduction of the repressive histone mark, H3K9me2. Similar effects were observed in vitro by overexpression of the histone di/tri-methyl demethylase KDM4B. Notably, forced induction of cell cycle activity by overexpression of cyclin/cyclin-dependent kinase significantly reduced H3K9me2 levels, in vitro. Together, these data point to a key role of H3K9me2 and its deposition by Ehmts in post-natal suppression of proliferation. Targeting this repressive mark could provide a strategy to enhance cardiac repair for therapeutic benefit.
Short-term outcomes of laparoscopy-assisted versus open surgery for low rectal cancer (LASRE): A multicenter, randomized, controlled trial.
Authors: Pan Chi, Xiangqian Su, Jianmin Xu, Huizhong Qiu, Ziqiang Wang, Liang Kang, Haijun Deng, Weiping Chen, Qingtong Zhang, Xiaohui Du, Chunkang Yang, Yincong Guo, Ming Zhong, Kai Ye, Jun You, Dongbo Xu, Xinxiang Li, Zhiguo Xiong, Kaixiong Tao, Ke-Feng Ding
Journal: Journal of Clinical Oncology (2022)

3516 Background: The efficacy of laparoscopic versus open surgery for low rectal cancer has not yet been established. We aimed to evaluate whether laparoscopic surgery is non-inferior to open surgery for low rectal cancer in terms of oncologic outcomes. Methods: LASRE trial (NCT01899547) is a multicenter, noninferiority, randomized controlled trial being conducted in 22 tertiary hospitals across China. Patients with low rectal cancer and without evidence of pelvic lateral lymph nodes or distant metastasis were randomly assigned (2:1) to laparoscopic or open surgery. The primary outcome was 3-year disease-free survival (DFS). Secondary outcomes included pathological outcomes, 30-day postoperative complications, 30-day mortality, overall survival (OS), and quality of life. The target sample size was 1065 patients. The short-term pathological, surgical, and postoperative recovery outcomes, analyzed in a modified intention-to-treat population (mITT). Results: Between November 12, 2013, and June 6, 2018, 1070 patients were randomized into laparoscopic (n = 712) or open surgery (n = 358) groups; 1039 were included in the mITT analysis (685 in laparoscopic and 354 in open group). Seventeen patients (2.5%) in the laparoscopic group required conversion to open surgery. There were no significant between-group differences in the rates of complete mesorectal excision (85.3% vs. 85.8%; p = 0.777), negative circumferential resection margins (98.2% vs. 99.7%; p = 0.085), negative distal resection margins (99.4% vs. 100%; p = 0.362), and numbers of retrieved lymph nodes (13.0 vs. 12.0; p = 0.394). The laparoscopic surgery group exhibited a shorter time to first flatus (40.4 vs. 44.8 hours; p = 0.006), time to first defecation (61.2 vs. 66.3 hours; p = 0.031), duration of analgesic use (45.0 vs. 48.0 hours; p = 0.001), and duration of hospitalization (8.0 vs. 9.0 days; p = 0.008) compared to the open surgery group. The postoperative complication rates were 13.0% and 17.2% in the laparoscopic and open surgery groups, respectively (p = 0.065). There was no incidence of 30-day mortality. Conclusions: In patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons can provide pathological outcomes comparable with those of open surgery in terms of complete mesorectal excision and negative resection margins, rapid postoperative recovery, and fewer postoperative complications. Clinical trial information: NCT01899547.
LINC-02. Gamma Knife Radiosurgery as an efficacious treatment for Pediatric Central Nervous System Tumors: A Retrospective Study of 61 Neoplasms
Authors: Bhavya Pahwa, Deepak Agrawal
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Brain tumors have an incidence of 1.15 to 5.14 cases per 100,000 children and are associated with significant morbidity and mortality. Radiosurgery has become a promising approach to manage these pediatric CNS tumors. The aim of the present study was to analyse the efficacy of radiosurgery in the treatment of a variety of pediatric tumors of CNS METHODS: This retrospective study was conducted from 1997-2012 at a single Neurosurgery centre. All paediatric patients (≤ 18 years of age) with CNS tumours who were treated with gamma knife radiosurgery (GKRS) and had a minimum follow up of 6 months were included in the study. Patients with lesions other than tumours were excluded. Clinical, radiological and GKRS planning data was collected and analysed in all patients. RESULTS: A total of 76 children with brain tumors had GKRS during the study period. Of these, 40 children (with 61 neoplasms) had follow up available and were included in the study. The mean age was 16 years (6-18 years). 17 patients received primary GKRS, 20 patients received secondary and 3 patients received both. The median tumor volume was 3.3cm3 (0.14 - 38.9 cm3). The mean dose was 12.56 Gy at 50% isodose line. The majority of the tumors were Meningioma (n=20) followed by Acoustic Schwannoma (n=17). The mean treatment time was 67.04 minutes. 33 tumors responded favourably to GKRS, 24 showed a stable size, 3 had no response while 1 progressed requiring surgery. CONCLUSION: GKRS has the potential to become an indispensable tool in the management of pediatric brain neoplasms
MEDB-22. iPSC-derived cerebellar organoid model for hereditary genetic predisposition in SHH-medulloblastoma
Authors: Frederik Manz, Daniel Haag, Stefan M Pfister, Lena Kutscher
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is one of the most common malignant embryonal brain tumors in children. Medulloblastomas of the Sonic Hedgehog (SHH) group arise from excessive proliferation of granule neuron progenitor (GNP) cells during cerebellar development. Genetic predisposition accounts for nearly 40% of all pediatric SHH-medulloblastomas. Recently, ELP1, a novel predisposition gene, was shown to be germline mutated in 15% of SHH-medulloblastoma patients. ELP1 encodes the scaffolding member of the Elongator complex and is required for efficient translation. Heterozygous mutations in ELP1 have been associated with the neural disorder Familial Dysautonomia, but not cancer. ELP1-associated medulloblastomas frequently harbor somatic PTCH1 co-mutations. It remains unclear how ELP1 affects the GNP lineage during normal cerebellar development and tumorigenesis in pediatric SHH-medulloblastoma patients. To characterize ELP1 mutations in the GNP lineage in vitro, we established a cerebellar organoid model from human induced pluripotent stem cells (iPSCs). We genetically inserted an EGFP reporter downstream of the endogenous GNP-specific ATOH1 locus in control iPSCs and generated cerebellar organoids according to published protocols. Marker gene and protein expression levels confirmed the cerebellar identity of the 3D model. Furthermore, activation of the EGFP reporter in single cells within the organoid highlighted the specification of putative GNPs. Next, we will determine the specific cell state of putative iGNPs and compare to human GNPs identified in our scRNAseq cerebellum atlas. To analyze tumorigenesis through ELP1 loss, we will introduce patient-specific ELP1mutations into ATOH1-EGFP iPSCs. Cerebellar organoids derived from ELP1-, PTCH1-deficient and control iPSCs will serve as models to study GNP proliferation, differentiation, apoptosis and tumor formation. Combining genome editing, in vitro 3D differentiation and functional studies, we will characterize the novel predisposition gene ELP1in GNPs during cerebellar development. In addition, we will determine the interplay of ELP1and PTCH1 co-mutations, predisposing SHH-medulloblastoma formation.
Access to definitive treatment and survival for intermediate-risk and high-risk prostate cancer at hospital systems serving health disparity populations.
Authors: Muhieddine Labban, David-Dan Nguyen, Logan Briggs, Alexander P Cole, Stuart R. Lipsitz, Hari S. Iyer, Timothy Rebbeck, Joel S. Weissman, Toni K. Choueiri, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2022)

6555 Background: Socioeconomic and racial disparities in prostate cancer (PCa) can be attributed to patient-level and physician-level factors. However, there is growing interest in investigating the role of the facility of care in driving cancer disparities. Therefore, we sought to examine receipt of guideline-concordant definitive treatment, time to treatment initiation (TTI), and survival for men with PCa receiving care at hospital systems serving health disparity populations (HSDPs). Methods: We conducted a retrospective analysis of the National Cancer Database (2004-2016) among men with intermediate-risk or high-risk PCa eligible for definitive treatment. The primary outcomes were receipt of definitive treatment and TTI within 90 days of diagnosis. The secondary outcome was survival. We defined HSDPs as minority-serving hospitals – facilities in the highest decile of proportion of Non-Hispanic Black (NHB) or Hispanic cancer patients – and/or high-burden safety-net hospitals – facilities in the highest quartile of proportion of underinsured patients. We used mixed-effect models with facility-level random intercept to compare outcomes between HSDPs and non-HSDPs among the entire cohort and among men who received definitive treatment. We evaluated interactions between HSDP status and race for each of the outcomes. Results: The cohort included 821,931 men with intermediate-risk or high-risk PCa. We included 968 non-HSDPs (72.2%) and 373 HSDPs (27.8%) facilities. Treatment at HSDPs was associated with lower odds of receipt of definitive treatment (aOR 0.64; 95% CI 0.57-0.71; p &lt; 0.001), lower odds of TTI within 90 days of diagnosis (aOR 0.74; 95% CI 0.68-0.79; p &lt; 0.001), and worse survival (aHR 1.05; 95% CI 1.02-1.09; p = 0.003). However, no difference was found in survival among patients who received definitive treatment. NHB men at HSDPs had also worse outcomes than NHB men treated at non-HSDPs as well as NHW men treated at HSDPs (Table). Conclusions: Patients treated at HSDPs were less likely to receive timely definitive treatment and had worse survival. NHB men have worse outcomes than NHW at HSDPs. NHB men with PCa remain largely disadvantaged since they are more likely to be treated at hospitals with worse outcomes and have worse outcomes than other patients at those same institutions. [Table: see text]
Abemaciclib in metastatic or locally advanced anaplastic thyroid cancer.
Authors: Vishesh Khanna, Cristy Miles, Vandana Sundaram, Siddharth Sheth, Martina Steffen, Savanna Biedermann, Dhayoung Jun, Elizabeth Winters, Saad A. Khan
Journal: Journal of Clinical Oncology (2022)

TPS6112 Background: Anaplastic thyroid cancer (ATC) is a rare and lethal tumor of thyroid epithelium, with disease-specific mortality approaching 100%. ATC accounts for &gt; 50% of the 1200 annual deaths attributable to thyroid cancer. In the pre-molecular era, treatment options were largely ineffective, reflected in a median overall survival of 3-4 months following diagnosis. Outcomes have improved in BRAF V600E-mutated ATC with the FDA approval of dabrafenib and trametinib (Subbiah et al. JCO, 2018). However, a significant need exists for patients with BRAF wild-type tumors and patients with BRAF-mutated tumors who progress following treatment with BRAF-directed therapies. Abemaciclib is a CDK4/6 inhibitor currently FDA-approved in combination with endocrine therapy for hormone-positive breast cancer. Genomic analyses of ATC have indicated the presence of an intact Rb (Retinoblastoma) expression as well as the existence of CDKN2A (the gene encoding human p16) mutations in up to 32% of patients with ATC (Khan et al., Head Neck, 2019). Moreover, Lee et al. in 2008 reported undetectable p16 levels in 24 out of 27 (89%) patients with ATC. Low p16 levels would be expected to result in accelerated S phase entry, leading to uncontrolled ATC growth. Finally, studies in mouse xenograft models have demonstrated that ribociclib (a CDK4/6 inhibitor) slows proliferation and induces apoptosis of ATC cells (Lee et al., Cancer Letters, 2018). These molecular alterations and pre-clinical data provide a mechanistic rationale by which to evaluate CDK4/6 inhibitors in ATC and, to date, no CDK4/6 inhibitors have been evaluated in thyroid cancer. Methods: This multicenter, single-arm Phase 2 study will evaluate the safety and efficacy of treatment with abemaciclib in patients with histologically confirmed unresectable or metastatic ATC, using an optimal Simon two-stage design. Patients with BRAF V600E+ ATC must have progressed on or have an intolerance to dabrafenib and trametinib. The study intervention is abemaciclib 200 mg orally twice daily. The primary endpoint is overall response rate at eight weeks from the start of treatment. Secondary endpoints include progression-free survival and overall survival. Currently, 6 patients have been enrolled. Planned genomic analysis will be conducted to identify potential predictive biomarkers. Clinical trial information: NCT04552769.
Functional remodeling of perinuclear mitochondria alters nucleoplasmic Ca2+ signaling in heart failure
Authors: J Voglhuber, M Holzer, S Radulovic, PN Thai, N Djalinac, I Matzer, M Wallner, H Bugger, A Zirlik, G Leitinger, EN Dedkova, DM Bers, S Ljubojevic-Holzer
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): BioTechMed-Graz Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure (HF) development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) vs. perinuclear (PN) mitochondria during the development of HF. Here, we use multiple approaches to examine the morphology and functional properties of IF vs. PN mitochondria in pressure overload-induced cardiac remodeling in mice, and in non-failing and failing human cardiomyocytes. We could demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to changes in mitochondrial membrane potential (ΔΨm), ROS generation and impairment in Ca2+ uptake compared to IF mitochondria at baseline and under physiological stress protocol. We also demonstrated, for the first time, that under normal conditions PN mitochondrial Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and prevents nucleoplasmic Ca2+ overload. Loss of PN mitochondria Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ signaling and alleviation of altered excitation-transcription, which could be an important therapeutic approach to prevent adverse cardiac remodeling.
Bladder biopsies to assess treatment response after intravesical Bacillus Calmette-Guerin induction cycle: Are they necessary?
Authors: G.M. Busetto, U.G. Falagario, B. Calò, F. Sanguedolce, M. Chirico, C. Bettocchi, G. Carrieri, L. Cormio
Journal: European Urology (2022)